Novel imaging biomarker for detection of regional cardiovascular inflammation using Positron Emission Tomography (PET)
Inflammation plays a key role in a number of different pathologies throughout the body. In our group, we are interested in developing PET imaging approaches which will allow the non-invasive assessment of inflammation in a range of cardiovascular and neurological diseases. We are currently developing a PET radiotracer, [18F]LW223, which targets the widely studied inflammatory marker 18 kDa translocator protein (TSPO) without susceptibility to a single nucleotide polymorphism (rs6971) in TSPO gene. We are currently at the stage of validating the use of [18F]LW223 to image TSPO expression in health and its dynamics in myocardial infarction and dementia. Our research is primarily driven by findings obtained from studying small animal models, but we also aim to evaluate the translational potential of [18F]LW223 using well characterised post-mortem human tissues.
Our colorful research on the BBC News: “Blood-Brain Barrier Rainbow”
Myocardial fibrosis and left ventricular remodelling in cardiovascular disease
Tissue inflammation and fibrosis following cardiovascular injury are two key fundamental processes involved in healing and remodelling. They are intimately involved in the left ventricular remodelling response to acute myocardial infarction, and are a major determinant of the subsequent progression to heart failure. Our reserach aims to understand and to characterise the pathophysiology and time course of collagen synthesis in the remodelling myocardium using a model of myocardial infarction. In order to achieve this, we will use 18F-fluoroprolines and PET imaging as biomarker of collagen biosynthesis, which can be readily translatable for clinical application for the same condition. This work will establish novel cardiovascular positron-emitting radiotracers for clinical application, with the potential to improve the characterisation of cardiovascular injury and repair, and enable the development of novel therapeutic strategies to inhibit maladaptive fibrosis implicated in the pathogenesis of cardiovascular disease.
Imaging myelination/remyelination processes with Positron Emission Tomography (PET) and a selective sphingosine-1-phosphate-5 (S1P5) radiotracer
Sphingosine-1-Phosphate (S1P) receptors are a family of G protein coupled receptors expressed widely across the body. Our group has an interest in S1P5 as it holds particular significance in Multiple Sclerosis (MS). S1P5 is thought to be expressed almost exclusively on oligodendrocytes in the central nervous system. S1P5 is targeted by the MS drug FYT720, albeit secondary to FYT720’s effect on the S1P1 receptor, yet the role of S1P5 in demyelinating diseases is not clearly defined. Further evidence on S1P5 distribution and effect on oligodendrocyte biology is required. Our research ultimately aims to develop and validate a radiotracer for S1P5 to allow for in vivo imaging of oligodendrocytes and ultimately to develop a greater understanding of S1P5 role in normal physiology and during disease.
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Publications stemming from this programme of research can be found HERE
Enabling advance imaging of synaptic function in living males and females over the course of the lifespan with Positron Emission Tomography (PET)
Synapses are damaged in over 130 different brain diseases and yet thus far there are no reliable ways to measure synaptic structure or function in vivo in a preclinical or clinical setting. The recent discovery of promising Positron Emission Tomography (PET) radiotracers for imaging synapses, by targeting the synaptic vesicle glycoprotein 2A (SV2A), has the potential to transform clinical diagnosis, neuropathology, drug development and treatment of multiple brain diseases. Two major bottlenecks to deliver on this promise are: (1) the unavailability of high-yield and high-molar activity [18F]MNI1126, the lead SV2A PET radiotracer; and (2) the lack of a quantitatively accurate and validated SV2A brain PET atlas during normal aging in rodent models. This project will generate synthetic routes and radiochemistry methods for efficient production of [18F]MNI1126, it will develop detailed template resources for quantitative analysis of SV2A PET signal in different brain regions over the course of natural aging in the rat and mouse, and it will validate SV2A PET in vivo outcomes at unprecedented scale and resolution using synaptome mapping technology. The development of SV2A PET technology proposed in this award will catapult the use of quantitative SV2A PET in many brain diseases in humans and model organisms.
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Drug risk assessment and repurposing using biomimetic chromatography and “body-on-chip” technology
Drug discovery pipelines can be lengthy, expensive and prone to a high degree of attrition with few drug candidates successfully reaching the market. Animal testing has been amply used to select lead drug candidates for first-in-Man clinical studies. Although the use of animals can be useful to assess drug distribution, metabolism and therapeutic effects, species differences versus humans often decrease the translational success rate of a new drug. Moreover, the use of animals at early stages of drug screening or during repurposing exercises can be expensive, can be impractical when handling large libraries of prospective drug candidates and can have low scientific value at the cost of a high number of animals used. Therefore, there is a need to design more efficient drug discovery pipelines and to increase confidence on selection of the lead compounds at early stages of the process. This project will investigate the use of biomimetic chromatography as a fast, economic and high-throughput platform to screen and rank compounds’ physicochemical properties, drug interaction with silence sites, and binding to human plasma proteins. In this project we will couple biomimetic chromatography with a modified body-on-chip technology to screen compounds’ affinity to different human cell targets (to aid drug risk assessment and repurposing exercises), characterise multi-organ biodistribution and metabolism, and predict drug success in humans. Validation of the new methodology will be done by comparing it with gold-standard in vivo outcome measurements of the same drugs already tested in humans using micro-dosing Positron Emission Tomography (PET) imaging.
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Kinetic modelling and analysis of total-body PET imaging datasets
New imaging technologies are allowing researchers to evaluate molecular changes in a living organism at organ level or in the whole body. This can be transformative to the way biologists study disease development and progression as well as the way new treatments are developed. A technique called Positron Emission Tomography or PET is a medical imaging technique capable of quantifying molecular changes in a living organism. This project will study how different organs and systems in the body are interconnected with each other based on their molecular connectome profiles measured using total-body PET imaging. This CZI-funded project would allow our group to develop new methods for analysis of complex PET images to derive a whole-body “molecular fingerprint” unique to each individual. Furthermore, with CZI support we will be able to teach the next generation of imaging biologists what PET techniques are and how to use them to support their research.
Standardisation of preclinical PET/CT protocols across multiple research centres
Preclinical data generated by different imaging centres can be difficult to compare due to the lack of standardisation of PET/CT imaging parameters. This also impacts on the ability to translate preclinical findings to clinical trials. This study: (1) quantitatively assesses the variability of current preclinical PET/CT acquisition and reconstruction protocols routinely used across multiple centers and scanners; and (2) proposes acquisition and reconstruction PET/CT protocols for standardization of multi-center data, optimized for routine scanning in preclinical PET/CT laboratory.
Results from this research were published in the Journal of Nuclear Medicine and featured as top story of the October 2019 SmartBrief from the Society of Nuclear Medicine and Molecular Imaging (SNMMI).